Breast cancer cells frequently disseminate to the bone marrow, where they either induce
osteolysis or enter a dormant state. Downregulation of
leukemia inhibitory factor receptor (LIFR), a known
breast tumor suppressor, enables otherwise dormant MCF7 human
breast cancer cells to become aggressively osteolytic.
Hypoxia (low
oxygen tensions), which may develop in
tumors as a pathological response to the metabolic demands of the proliferating cells and as a physiological state in the bone, downregulates LIFR in
breast cancer cells independent of
hypoxia-inducible factor (HIF) signaling. However, the mechanism by which LIFR is repressed in
hypoxia is unknown.
Histone deacetylase (
HDAC) inhibitors stimulate LIFR by increasing
histone acetylation in the proximal promoter and induce a dormancy phenotype in
breast cancer cells inoculated into the mammary fat pad. We therefore aimed to determine whether
hypoxia alters
histone acetylation in the LIFR promoter, and whether
HDAC inhibitors effectively stimulate LIFR in
breast cancer cells residing in hypoxic microenvironments. Herein, we confirmed that disseminated MCF7 cells became hypoxic in the bone and that
hypoxia increased the epigenetic transcriptional repressor H3K9me3 in the distal LIFR promoter while H3K9ac, which promotes transcription, was significantly reduced. Furthermore,
HDAC inhibitor treatment rescued hypoxic repression and dramatically increased expression of LIFR, p38β, and p21, which regulate
tumor dormancy. In a second model of LIFR repression, in which
parathyroid hormone-related protein (
PTHrP) suppresses LIFR expression, we found that
PTHrP binds to the distal LIFR promoter, and that
PTHrP suppression of LIFR
protein is similarly reversed by
HDAC inhibitor treatment. Together, these data suggest that
HDAC inhibitors stimulate LIFR regardless of the way it is repressed by the microenvironment.